Helicobacter pylori and Gastric Lymphoma Marta Pisarska DT204/2

Overview Gastric Lymphoma B-cells Extranodal Marginal Zone Lymphoma of Mucosa Associated Tissue Helicobacter pylori infection and it’s association with this cancer Diagnosis and confirmation of presence of H.pylori Treatment of Gastric Lymphoma with focus on H. pylori eradication

Gastric Lymphoma „Tumour of haematological cells, which develops within the lymphatic system of the gastric area” Can affect lymphatic organs or be extranodal Divided into Hodgkin's and Non Hodgkins types of lymphomas Indolent or Aggressive Affects T and B lymphocytes http://www.thefreedictionary.com/lymphoma http://www.pathologyatlas.ro/reed-sternberg-cell.php http://radiopaedia.org/articles/gastric_lymphoma Zullo A, Hassan C, Ridola L, Repici A, Manta R, AndianiA. Gastric MALT lymphoma:old and new insights. Annals of Gastroenterology. 2014; 27(1): 27–33.

Extranodal Gastric Lymphoma Extranodal lymphoma occurs most commonly in the gastric area In 2/3 of cases it affects the stomach Two main types of primary extranodal gastric lymphoma are identified: Extranodal Marginal Zone Lymphoma of Mucosa Associated Tissue (MALT) Diffuse Large B-cell Lymphoma of Stomach (DLBCL) Other less common types include Follicular and Mantle cell gastric lymphomas. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Lymphomanon-Hodgkin/TypesofNHL/DiffuselargeB-cell.aspx http://radiopaedia.org/articles/gastric_lymphoma Witkowska M, Smolewski P. Helicobacter pylori infection, Chrinic Inflammation, and Genomic Transformations in Gastric MALT Lymphoma. Mediators of Inflammation.2013. 2013:523170

Extranodal Marginal Zone Lymphoma of MALT „Arises from MALT tissue rich in B-lymphocytes, due to a normal immune response to chronic inflammation or due to an autoimmune disease” Can occur in any organ H.pylori infection is considered to be the most important risk factor of this type of lymphoma http://radiopaedia.org/articles/gastric_lymphoma http://www.myvmc.com/diseases/lymphoma-of-the-stomach-gastric-lymphoma/ http://www.cancerresearchuk.org/cancer-help/type/non-hodgkins-lymphoma/about/risks/definite-risk-factors-for-non-hodgkins-lymphoma Witkowska M, Smolewski P. Helicobacter pylori infection, Chrinic Inflammation, and Genomic Transformations in Gastric MALT Lymphoma. Mediators of Inflammation.2013. 2013:523170

Figure 1: Micrograph showing H. pylori with unipolar flagella H.pylori infection Caused by a gram negative, spiral bacteria Once it colonises the stomach, it remains there for a lifetime, causing chronic inflammation, unless it is treated Bacteria is present in 85-92% of patients with MALT lymphoma In 80% of cases patients are asymptomatic Witkowska M, Smolewski P. Helicobacter pylori infection, Chrinic Inflammation, and Genomic Transformations in Gastric MALT Lymphoma. Mediators of Inflammation.2013. 2013:523170 Kim S.S, Ruiz V.E, Carroll, J.D, Moss, S.F. Helicobacter pylori in the pathogenesis of gastric cancer and gastric lymphoma. Cancer Letters. 2012; 305(2): 228-238 http://pathmicro.med.sc.edu/fox/enterobact.htm Figure 1: Micrograph showing H. pylori with unipolar flagella

How does H.pylori contribute to MALT Lymphoma? 1. Persisting presence of H.pylori causes chronic inflammation 2. Inflammation leads to infiltration of immune cells in order to remove the microorganism - B and T lymphocytes – production of antibodies - Macrophages –production of APRIL - Neutophils – production of reactive oxygen species 3. Reactive oxygen species cause damage to the DNA of B-lymphocytes 4. May lead to overexpression of oncogenes or alteration of signalling pathways Pereira M I, Medeiros J.A. Role of Helicobacter Pylori in gastric mucosa-associated lymphoid tissue lymphomas. World J Gastroenterol. 3014; 20(3) 684-698

Detection of MALT lymphoma Diagnosis is based on various tests Endoscopy with biopsy– investigation of any changes to the stomach lining and obtaining a tissue sample where appropriate Histology Investigation– Routine histology - Immunohistochemistry (positive for CD20,coexpression of CD 43/ BLC2 Negative for CD5 CD10,CD 23, cyclin D1) Cytogenetic and Molecular Tests - to investigate genetic aberrations, especially t(11;18) (q21;q21) translocation using methods like FISH or PCR If histology results are negative for H.pylori, further tests are required: Rapid Urea Breath Test Blood tests Faecal Test Witkowska M, Smolewski P. Helicobacter pylori infection, Chrinic Inflammation, and Genomic Transformations in Gastric MALT Lymphoma. Mediators of Inflammation.2013. 2013:523170 Pereira M I, Medeiros J.A. Role of Helicobacter Pylori in gastric mucosa-associated lymphoid tissue lymphomas. World J Gastroenterol. 3014; 20(3) 684-698 http://www.myvmc.com/diseases/lymphoma-of-the-stomach-gastric-lymphoma/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418529/ http://ellishospital.adam.com/content.aspx?productId=49&pid=49&gid=150484

Endoscopy http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961970/figure/F1/ Figure 2: Pictures showing different appearances of gastric MALT Lymphoma investigated using endoscope

B: Positive immunohistochemistry stain using CD20 Histology http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961970/figure/F2/ Figure 3: Images showing Histology tissue architecture of gastric MALT lymphoma A: H and E stain B: Positive immunohistochemistry stain using CD20

Treatment Treatment is based on the presence/ absence of H.pylori, invasion stage, age, nodal status, etc. Many successful treatments are available: Eradication of H.pylori First line treatment is H.pylori Used in low grades MALT lymphomas with a big success Radiotherapy Chemotherapy Surgery Immunotherapy Witkowska M, Smolewski P. Helicobacter pylori infection, Chrinic Inflammation, and Genomic Transformations in Gastric MALT Lymphoma. Mediators of Inflammation.2013. 2013:523170

H.Pylori Eradication Eradication is usually a dual or triple therapy which uses a combination of proton pump inhibitor and antibiotics. 1. Proton pump inhibitor Causes reduction of secretion of acids in the stomach Esomeprazole, Lansoprazole, Omeptazole 2. Antibiotics Combination of 2 or 3 antibiotics are used Metronidazole and Clarithromycin or Amoxicillin + Clarithromycin 3. Bismuth Has similar effects as iron deprivation http://www.mims.co.uk/mims_specialist/article/882106/Combination-Regimens-Eradication-Hpylori-NICE-guidance/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC415606/ Zullo A, Hassan C, Ridola L, Repici A, Manta R, AndianiA. Gastric MALT lymphoma:old and new insights. Annals of Gastroenterology. 2014; 27(1): 27–33. Bland MV, Ismail S, Heinemann JA, Keenan JI. The action of bismuth against Helicobacter pylori Mimics but is not caused by intracellular iron deprivation. Antimicrobial Agents and Chemotherapy. 2004; 48(6): 1983-1988

H.Pylori Eradication After treatment 8/10 patients experiencing regression of the cancer Therapy is administrated usually for 1- 2 weeks Successful if Tumour hasn’t spread into the stomach wall Tumour is absent in the lymph nodes H.pylori is not resistant to antibiotics Patient is t(11;18) negative Zullo A, Hassan C, Ridola L, Repici A, Manta R, AndianiA. Gastric MALT lymphoma:old and new insights. Annals of Gastroenterology. 2014; 27(1): 27–33.

Summary There’s strong evidence that H. pylori is strongly linked with Gastric lymphomas - especially with MALT lymphoma Most important risk of developing gastric lymphoma is H.pylori infection Many Tests are available to diagnose this cancer Treatment has very high successful rate, currently new treatment using antibodies is under investigatigation